PROJECT SUMMARY Current therapy for advanced heart failure (HF) is limited and new treatment is needed since the mortality and morbidity of subjects with this form of heart disease remain high. Effort aimed at enhanced healing of failing heart by cardioprotection represents a novel approach. The specific background for the proposed project is that we have identified the endogenous cardiac P2X receptor as a new therapeutic target for cardioprotection. The cardiac P2X4 receptor is an essential and important subunit of the endogenous cardiac P2X receptor. A small molecule drug substance MRS2339 activating cardiac P2X receptors has proven preclinical efficacy in animal models of advanced HF and is without safety concerns in the Investigational New Drug (IND)- enabling studies in rat and dog. Cornovus is a company, in collaboration with its academic partner University of Connecticut School of Medicine?s cardiology research laboratory and Laboratory of Bioorganic Chemistry of the National Institute of Diabetes, Digestive and Kidney Diseases of NIH, is well-positioned to apply for an IND to the Food and Drug Administration (FDA) should the proposal is awarded. The objective of the grant is to further develop process chemistry for bulk cGMP manufacturing of the clinical lot of MRS2339 and its drug product based on the current formulation as well as to perform FDA-requested in vitro studies on cardiac ion channels and on potential mitochondrial toxicity by MRS2339 and its metabolite MRS1873. Cornovus has already improved the scale-up process chemistry in producing hundred gram quantity for GLP safety studies and has ruled out any effect on the human ether--go-go-related gene (hERG) ion channel by both compounds. The proposed studies should add to scientific knowledge on the chemistry and pharmacology of both compounds and may also yield new insights into the science of nucleotide and nucleoside. The proposal should also satisfy the regulatory requirements to move this new drug into first-in-human clinical study, as we anticipate new benefit to patients with advanced HF.